The goal of the proposed research remains characterization of the peripheral innervation to the eye by integration of histochemical, anatomical and biochemical methods. We shall extend our recent studies of the intraocular distribution of nerve fibers producing nitric oxide to other species, shall seek evidence for novel isozymes of its biosynthetic enzyme and study the potential role of nitric oxide in retinal ischemia and corneal denervation. Continuing our longstanding study of intraocular peptidergic nerve fibers, we propose analysis that includes ocular and related cranial tissues and further searches for novel neuropeptides. We shall focus on the parasympathetic component of the ocular innervation as the most likely to the parasympathetic component of the ocular innervation as the most likely to provide novel insights for future physiologic and pharmacologic studies, not only continuing study of primary neural messengers but also addressing the intraocular distribution of receptors to selected parasympathetic messenger molecules. We also shall seek evidence for novel neuroregulatory or paracrine mechanisms in he eye. Using modern methods, we shall integrate findings in the eye with the neurochemical organization of the relevant cranial ganglia to achieve a comprehensive understanding of the peripheral innervation of the eye. Our identifications of the primary neural messengers and their interrelationships provide an essential basis for understanding the regulatory mechanisms that govern ocular physiology. Furthermore, given the importance of neural mechanisms in ocular pharmacology, such studies provide the basis for understanding ophthalmic drugs and developing novel clinical therapies. The breadth of our pharmacologic perspective and the versatility of our methods will continue to produce results relevant to the physiology and therapy of important ocular disorders, such as glaucoma, circulatory disease, injury and inflammation.